EP0065909B1 - ((Pipéridyl-4)-2 alkyl-1 éthyl)-3 indoles et leur utilisation comme médicaments - Google Patents
((Pipéridyl-4)-2 alkyl-1 éthyl)-3 indoles et leur utilisation comme médicaments Download PDFInfo
- Publication number
- EP0065909B1 EP0065909B1 EP82400873A EP82400873A EP0065909B1 EP 0065909 B1 EP0065909 B1 EP 0065909B1 EP 82400873 A EP82400873 A EP 82400873A EP 82400873 A EP82400873 A EP 82400873A EP 0065909 B1 EP0065909 B1 EP 0065909B1
- Authority
- EP
- European Patent Office
- Prior art keywords
- piperidyl
- compounds
- formula
- serotonin
- ether
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
- 150000002475 indoles Chemical class 0.000 title description 2
- 239000000825 pharmaceutical preparation Substances 0.000 title 1
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 claims description 32
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 31
- 150000001875 compounds Chemical class 0.000 claims description 14
- 238000000034 method Methods 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 5
- 239000003814 drug Substances 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 4
- 239000004215 Carbon black (E152) Substances 0.000 claims description 3
- 238000009835 boiling Methods 0.000 claims description 3
- 229930195733 hydrocarbon Natural products 0.000 claims description 3
- 150000002430 hydrocarbons Chemical class 0.000 claims description 3
- 239000003112 inhibitor Substances 0.000 claims description 3
- 239000002253 acid Substances 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 229910052987 metal hydride Inorganic materials 0.000 claims description 2
- 150000004681 metal hydrides Chemical class 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 claims description 2
- 150000007513 acids Chemical class 0.000 claims 1
- 239000002269 analeptic agent Substances 0.000 claims 1
- 230000002460 anti-migrenic effect Effects 0.000 claims 1
- 230000002785 anti-thrombosis Effects 0.000 claims 1
- 229940076279 serotonin Drugs 0.000 description 15
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 14
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 210000001772 blood platelet Anatomy 0.000 description 7
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 7
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 7
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- HGCIXCUEYOPUTN-UHFFFAOYSA-N cyclohexene Chemical compound C1CCC=CC1 HGCIXCUEYOPUTN-UHFFFAOYSA-N 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 5
- 239000002585 base Substances 0.000 description 5
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 4
- SADQVAVFGNTEOD-UHFFFAOYSA-N indalpine Chemical compound C=1NC2=CC=CC=C2C=1CCC1CCNCC1 SADQVAVFGNTEOD-UHFFFAOYSA-N 0.000 description 4
- 229950002473 indalpine Drugs 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- 238000004587 chromatography analysis Methods 0.000 description 3
- -1 diethyl ether) Chemical compound 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 230000007062 hydrolysis Effects 0.000 description 3
- 238000006460 hydrolysis reaction Methods 0.000 description 3
- VXWPONVCMVLXBW-UHFFFAOYSA-M magnesium;carbanide;iodide Chemical compound [CH3-].[Mg+2].[I-] VXWPONVCMVLXBW-UHFFFAOYSA-M 0.000 description 3
- 210000002569 neuron Anatomy 0.000 description 3
- WWPITPSIWMXDPE-UHFFFAOYSA-N para-chloroamphetamine Chemical compound CC(N)CC1=CC=C(Cl)C=C1 WWPITPSIWMXDPE-UHFFFAOYSA-N 0.000 description 3
- 230000000697 serotonin reuptake Effects 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- 239000007818 Grignard reagent Substances 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- 208000019695 Migraine disease Diseases 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical compound [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 description 2
- 229910052782 aluminium Inorganic materials 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 150000004795 grignard reagents Chemical class 0.000 description 2
- 239000012442 inert solvent Substances 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 2
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 2
- SIAPCJWMELPYOE-UHFFFAOYSA-N lithium hydride Chemical compound [LiH] SIAPCJWMELPYOE-UHFFFAOYSA-N 0.000 description 2
- 229910000103 lithium hydride Inorganic materials 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- MTJGVAJYTOXFJH-UHFFFAOYSA-N 3-aminonaphthalene-1,5-disulfonic acid Chemical compound C1=CC=C(S(O)(=O)=O)C2=CC(N)=CC(S(O)(=O)=O)=C21 MTJGVAJYTOXFJH-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 1
- 239000005695 Ammonium acetate Substances 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 125000003158 alcohol group Chemical group 0.000 description 1
- 150000004791 alkyl magnesium halides Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 229940043376 ammonium acetate Drugs 0.000 description 1
- 235000019257 ammonium acetate Nutrition 0.000 description 1
- 208000022531 anorexia Diseases 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 239000000935 antidepressant agent Substances 0.000 description 1
- 229940005513 antidepressants Drugs 0.000 description 1
- 229940054051 antipsychotic indole derivative Drugs 0.000 description 1
- 229960004676 antithrombotic agent Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 206010061428 decreased appetite Diseases 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 210000005260 human cell Anatomy 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 230000035873 hypermotility Effects 0.000 description 1
- BCGWQEUPMDMJNV-UHFFFAOYSA-N imipramine Chemical compound C1CC2=CC=CC=C2N(CCCN(C)C)C2=CC=CC=C21 BCGWQEUPMDMJNV-UHFFFAOYSA-N 0.000 description 1
- 229960004801 imipramine Drugs 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 206010027599 migraine Diseases 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 230000001537 neural effect Effects 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 150000003053 piperidines Chemical class 0.000 description 1
- 210000002381 plasma Anatomy 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 229940001470 psychoactive drug Drugs 0.000 description 1
- 239000004089 psychotropic agent Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000008929 regeneration Effects 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000000946 synaptic effect Effects 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- NQRYJNQNLNOLGT-UHFFFAOYSA-N tetrahydropyridine hydrochloride Natural products C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 1
- 239000003440 toxic substance Substances 0.000 description 1
- 230000002110 toxicologic effect Effects 0.000 description 1
- 231100000723 toxicological property Toxicity 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Definitions
- R represents an alkyl group having 1 to 3 carbon atoms and X represents a hydrogen or halogen atom, for example fluorine or chlorine.
- the compounds of general formula (II) can be prepared by action on the compounds of general formula: in which R and X have the same meanings as in formula (II) of a metal hydride, such as aluminum and lithium hydride, within an ether, such as diethyl ether or tetra -hydro-furan, or of a mixture of an ether and a hydrocarbon such as toluene, at a temperature between 0 ° C and the boiling point of the solvent used.
- a metal hydride such as aluminum and lithium hydride
- ether such as diethyl ether or tetra -hydro-furan
- a hydrocarbon such as toluene
- the hydrolysis of the reaction mixture must be carried out at low temperature (between 0 and 10 ° C) and in a pH zone between 5 and 7.
- Step d) consists in cutting the protective group B under conditions making it possible to avoid dehydration of the alcohol function of the chain.
- Cyclohexene is advantageously used for this purpose in the presence of aluminum chloride and palladium on carbon, at the boiling point of cyclohexene.
- the piperidine derivative of formula (V) can be prepared in 2 steps from piperidyl-4 acetic acid according to I. DE GRAW, J. Hetero. Chem., 3, 90 (1966).
- reaction mixtures obtained according to the various processes described above are treated according to conventional, physical (evaporation, extraction using a solvent, distillation, crystallization, chromatography, etc.) or chemical (salt formation and regeneration) methods. base, etc.) in order to isolate the compounds of formula (II) in the pure state.
- the compounds of formula (II) in the form of the free base can optionally be converted into addition salts with a mineral or organic acid by the action of such an acid in an appropriate solvent.
- a suspension of 16 g of aluminum and lithium hydride, 10 g of (piperidyl-4) -1 (p.toluenesulfonyloxy-1 indolyl-3) -2 propanol-2 is heated for 5 hours at 50 ° C. 300 ml of ether and 300 ml toluene.
- the starting product is prepared as follows: To a solution of methyl magnesium iodide prepared from 6.5 g of magnesium and 38.6 g of methyl iodide in 150 ml of ethyl ether, 17.6 g of indole dissolved in 100 ml of ether are added. The mixture is refluxed for 2 hours, then cooled to around 0 ° C. before adding dropwise with stirring a solution of 36.3 g of benzyloxycarbonyl-1 piperidyl-4 acetyl chloride (Ger patent. Offen. 2,618,152 ) in 300 ml of toluene; stirred for 2 hours at 10 ° C.
- This suspension is gradually added to a solution of methyl magnesium iodide prepared from 3.1 g of magnesium and 18.5 g of methyl iodide in 200 ml of ethyl ether.
- the mixture is stirred overnight at ambient temperature and hydrolysis at around 5 ° C. with 650 ml of an aqueous solution at 20% by weight of ammonium acetate.
- 35.5 g of (benzyloxycarbonyl-1 piperidyl-4) -1 (tosyl-1 indolyl-3) -2 propanol-2 are obtained.
- the results are expressed by an inhibitory dose 50% or 150 which represents the dose of product, in micromoles per liter, decreasing by 50% the uptake of serotonin.
- the products of the invention are therefore not only powerful inhibitors of serotonin reuptake (activities equivalent to that of indalpine) but also powerful serotonin-releasing agents, even more active than p-chloro- amphetamine.
- the acute toxicity of the products was determined in male CD mice, (Charles RIVER) orally.
- the compounds according to the invention behave as relatively little toxic substances.
- the product of Example 1 is non-toxic at a dose of 100 mg / kg in mice.
- the compounds of the invention and their pharmaceutically acceptable salts can be used in human therapy in the form of tablets, capsules, capsules, suppositories, ingestible or injectable solutions, etc. as reactors of the serotonin-dependent vacular tone, in particular for the treatment of migraines, as anti-thrombotic agents and as particularly rapid-acting thymoanaleptic drugs (because of their action on the release of serotonin).
- the dosage depends on the desired effects and the route of administration used. For example, orally, it can be between 15 and 250 mg of active substance per day, with unit doses ranging from 5 to 50 mg.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Indole Compounds (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR8110220A FR2506311A1 (fr) | 1981-05-22 | 1981-05-22 | ((piperidyl-4)-2 alkyl-1 ethyl)-3 indoles et leur utilisation comme medicaments |
| FR8110220 | 1981-05-22 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| EP0065909A1 EP0065909A1 (fr) | 1982-12-01 |
| EP0065909B1 true EP0065909B1 (fr) | 1984-12-12 |
Family
ID=9258784
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP82400873A Expired EP0065909B1 (fr) | 1981-05-22 | 1982-05-11 | ((Pipéridyl-4)-2 alkyl-1 éthyl)-3 indoles et leur utilisation comme médicaments |
Country Status (17)
| Country | Link |
|---|---|
| US (1) | US4416888A (xx) |
| EP (1) | EP0065909B1 (xx) |
| JP (1) | JPS57200384A (xx) |
| AR (1) | AR231445A1 (xx) |
| AU (1) | AU551047B2 (xx) |
| CA (1) | CA1183137A (xx) |
| DE (1) | DE3261524D1 (xx) |
| DK (1) | DK220882A (xx) |
| ES (1) | ES8307790A1 (xx) |
| FR (1) | FR2506311A1 (xx) |
| GR (1) | GR75841B (xx) |
| HU (1) | HU188171B (xx) |
| IL (1) | IL65474A (xx) |
| MA (1) | MA19482A1 (xx) |
| NO (1) | NO821699L (xx) |
| PT (1) | PT74917B (xx) |
| ZA (1) | ZA823492B (xx) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0429341A3 (en) * | 1989-11-20 | 1991-11-13 | Rhone-Poulenc Sante | Heterocyclic derivatives, their preparation and pharmaceuticals containing them |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB925429A (en) * | 1960-04-01 | 1963-05-08 | Irwin Neisler & Co | Indole derivatives |
| US3136770A (en) * | 1960-04-01 | 1964-06-09 | Neisler Lab Inc | Indolyl substituted piperidines |
| FR1289690A (fr) * | 1960-04-01 | 1962-04-06 | Irwin | Dérivés de l'indole |
| GB1023781A (en) * | 1962-02-01 | 1966-03-23 | Benger Lab Ltd | Substituted indoles and their preparation |
| US3471499A (en) * | 1965-12-03 | 1969-10-07 | American Home Prod | 1,4-bis-(2-indol-3-yl-ethyl)piperazines |
| US4208417A (en) * | 1978-06-29 | 1980-06-17 | Pharmindustrie | Indole derivatives and their use as anxiolytics |
-
1981
- 1981-05-22 FR FR8110220A patent/FR2506311A1/fr active Granted
-
1982
- 1982-04-12 IL IL65474A patent/IL65474A/xx unknown
- 1982-05-03 US US06/374,365 patent/US4416888A/en not_active Expired - Fee Related
- 1982-05-04 GR GR68057A patent/GR75841B/el unknown
- 1982-05-11 EP EP82400873A patent/EP0065909B1/fr not_active Expired
- 1982-05-11 DE DE8282400873T patent/DE3261524D1/de not_active Expired
- 1982-05-17 DK DK220882A patent/DK220882A/da not_active Application Discontinuation
- 1982-05-18 PT PT74917A patent/PT74917B/pt unknown
- 1982-05-19 AR AR289455A patent/AR231445A1/es active
- 1982-05-19 ZA ZA823492A patent/ZA823492B/xx unknown
- 1982-05-20 MA MA19688A patent/MA19482A1/fr unknown
- 1982-05-21 ES ES512473A patent/ES8307790A1/es not_active Expired
- 1982-05-21 AU AU84043/82A patent/AU551047B2/en not_active Ceased
- 1982-05-21 CA CA000403514A patent/CA1183137A/fr not_active Expired
- 1982-05-21 JP JP57086382A patent/JPS57200384A/ja active Pending
- 1982-05-21 NO NO821699A patent/NO821699L/no unknown
- 1982-05-21 HU HU821641A patent/HU188171B/hu unknown
Also Published As
| Publication number | Publication date |
|---|---|
| PT74917B (fr) | 1983-12-07 |
| CA1183137A (fr) | 1985-02-26 |
| GR75841B (xx) | 1984-08-02 |
| DK220882A (da) | 1982-11-23 |
| JPS57200384A (en) | 1982-12-08 |
| IL65474A (en) | 1985-08-30 |
| EP0065909A1 (fr) | 1982-12-01 |
| ZA823492B (en) | 1983-03-30 |
| AR231445A1 (es) | 1984-11-30 |
| DE3261524D1 (en) | 1985-01-24 |
| IL65474A0 (en) | 1982-07-30 |
| NO821699L (no) | 1982-11-23 |
| HU188171B (en) | 1986-03-28 |
| AU8404382A (en) | 1982-11-25 |
| AU551047B2 (en) | 1986-04-17 |
| FR2506311A1 (fr) | 1982-11-26 |
| US4416888A (en) | 1983-11-22 |
| MA19482A1 (fr) | 1982-12-31 |
| FR2506311B1 (xx) | 1983-12-16 |
| PT74917A (fr) | 1982-06-01 |
| ES512473A0 (es) | 1983-08-01 |
| ES8307790A1 (es) | 1983-08-01 |
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